EP0834507B1 - Substituierte Diamino-1,3,5-Triazinderivate - Google Patents

Substituierte Diamino-1,3,5-Triazinderivate Download PDF

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EP0834507B1
EP0834507B1 EP97202917A EP97202917A EP0834507B1 EP 0834507 B1 EP0834507 B1 EP 0834507B1 EP 97202917 A EP97202917 A EP 97202917A EP 97202917 A EP97202917 A EP 97202917A EP 0834507 B1 EP0834507 B1 EP 0834507B1
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alkyl
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amino
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EP0834507A1 (de
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Michael Joseph Janssen Res. Foundation Kukla
Donald W. Janssen Res. Foundation Ludovici
Paul Adriaan Jan Janssen
Jan Heeres
Henri Emiel Lodewijk Moereels
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Janssen Pharmaceutica NV
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
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    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
    • C07D251/18—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
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    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/32—Oxygen atoms
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    • C07—ORGANIC CHEMISTRY
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    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Claims (16)

  1. Verbindungen der Formel
    Figure 00390001
    und deren pharmazeutisch unbedenkliche Säureadditionssalze und stereochemisch isomere Formen, wobei
    R1 und R2
    jeweils unabhängig voneinander aus Wasserstoff; Hydroxy; Amino; C1-6-Alkyl; C1-6-Alkyloxy; C1-6-Alkylcarbonyl; C1-6-Alkyloxycarbonyl; Ar1; Mono- ode Di(C1-6-alkyl)amino; Mono- oder Di(C1-6-alkyl)aminocarbonyl; Dihydro-2(3H)-furanon; durch einen oder zwei Substituenten unabhängig voneinander ausgewählt aus Amino, Imino, Aminocarbonyl, Aminocarbonyl-amino, Hydroxy, Hydroxy-C1-6-alkyloxy, Carboxyl, Mono- oder Di(C1-6-alkyl)amino, C1-6-Alkyloxycarbonyl und Thienyl substituiertes C1-6-Alkyl ausgewählt sind; oder
    R1 und R2
    zusammen Pyrrolidinyl, Piperidinyl, Morpholinyl, Azido oder Mono- oder Di(C1-6-alkyl)amino-C1-4-alkyliden bilden können;
    R3
    Wasserstoff, Ar1, C1-6-Alkylcarbonyl, C1-6-Alkyl, C1-6-Alkyloxycarbonyl, durch C1-6-Alkyloxycarbonyl substituiertes C1-6-Alkyl steht; und
    R4, R5, R7 und R8
    jeweils unabhängig voneinander aus Wasserstoff, Hydroxy, Halogen, C1-6-Alkyl, C1-6-Alkyloxy, Cyano, Aminocarbonyl, Nitro, Amino, Trihalogenmethyl oder Trihalogenmethyloxy ausgewählt sind;
    R6
    für Cyano oder Aminocarbonyl steht;
    L
    für C1-10-Alkyl; C3-10-Alkenyl; C3-10-Alkinyl; C3-7-Cycloalkyl steht; oder
    L
    für C1-10-Alkyl steht, das durch einen oder zwei Substituenten unabhängig voneinander ausgewählt aus
    • a) C3-7-Cycloalkyl;
    • b) Indolyl oder durch einen, zwei, drei oder vier Substituenten, jeweils unabhängig voneinander ausgewählt aus Halogen, C1-6-Alkyl, C1-6-Alkyloxy, Cyano, Aminocarbonyl, Nitro, Amino, Trihalogenmethyl, Trihalogenmethyloxy, C1-6-Alkylcarbonyl, substituiertes Indolyl;
    • c) Phenyl oder durch einen, zwei, drei, vier oder fünf Substituenten, jeweils unabhängig voneinander ausgewählt aus Halogen, Hydroxy, C1-6-Alkyl, C1-6-Alkyloxy, Cyano, Aminocarbonyl, Nitro, Amino, Trihalogenmethyl, Trihalogenmethyloxy, C1-6-Alkylcarbonyl, substituiertes Phenyl; substituiert ist und
    Ar1
    für Phenyl oder durch einen, zwei oder drei Substituenten, jeweils unabhängig voneinander ausgewählt aus Halogen, C1-6-Alkyl, C1-6-Alkyloxy, Cyano, Nitro oder Trifluormethyl, substituiertes Phenyl steht.
  2. Verbindungen nach Anspruch 1, wobei R1 und R2 jeweils unabhängig voneinander aus Wasserstoff, C1-6-Alkyl, Ar1 oder Mono- oder Di(C1-6-alkyl)aminocarbonyl ausgewählt sind; oder R1 und R2 zusammen Pyrrolidinyl, Piperidinyl oder Morpholinyl bilden können; R3 für Wasserstoff, C1-6-Alkyl oder Ar1 steht; und Ar1 für Phenyl oder durch einen, zwei oder drei Substituenten, jeweils unabhängig voneinander ausgewählt aus Halogen, C1-6-Alkyl, C1-6-Alkyloxy, Cyano, Nitro oder Trifluormethyl, substituiertes Phenyl steht; und
    L
    für einen Rest der Formel
    Figure 00410001
    steht, wobei Alk für C1-6-Alkandiyl steht;
    Ra, Rb, Rc, Rd, Re, R4, R5, R7 und R8
    jeweils unabhängig voneinander ausgewählt sind aus Wasserstoff, Halogen, C1-6-Alkyl, C1-6-Alkyloxy, Cyano, Aminocarbonyl, Nitro, Amino, Trihalogenmethyl oder Trihalogenmethyloxy; oder
    Ra und Rb
    zusammen einen zweiwertigen Rest der Formel -CH=CH-NR9- -NR9-CH=CH- wobei R9 für Wasserstoff oder C1-4-Alkyl steht,
       bilden können.
  3. Verbindungen nach Anspruch 1 oder 2, wobei L für C3-10-Alkenyl oder C1-2-Alkyl, das durch einen oder zwei Substituenten unabhängig voneinander ausgewählt aus
    a) C3-7-Cycloalkyl ;
    b) Indolyl oder durch einen, zwei, drei oder vier Substituenten, jeweils unabhängig voneinander ausgewählt aus Halogen, C1-6-Alkyl, C1-6-Alkyloxy, Cyano, Aminocarbonyl, Nitro, Amino, Trihalogenmethyl, Trihalogenmethyloxy, C1-6-Alkylcarbonyl, substituiertes Indolyl;
    c) Phenyl oder durch einen, zwei, drei, vier oder fünf Substituenten, jeweils unabhängig voneinander ausgewählt aus Halogen, Hydroxy, C1-6-Alkyl, C1-6-Alkyloxy, Cyano, Aminocarbonyl, Nitro, Amino, Trihalogenmethyl, Trihalogenmethyloxy, C1-6-Alkylcarbonyl, substituiertes Phenyl, substituiert ist.
  4. Verbindungen nach einem der Ansprüche 1 bis 3, wobei L für 2,6-Dichlorphenylmethyl steht.
  5. Verbindungen nach einem der Ansprüche 1 bis 4, wobei NR1R2 nicht für Amino steht.
  6. Verbindungen nach Anspruch 1, wobei es sich bei den Verbindungen um 4-[[4-Amino-6-[(2,6-dichlorphenyl)methyl]-1,3,5-triazin-2-yl]amino]benzonitril; 4-[[4-[(2,6-Dichlorphenyl)methyl]-6-(hydroxyamino)-1,3,5-triazin-2-yl]amino]benzonitril und deren pharmazeutisch unbedenkliche Säureadditionssalze handelt.
  7. Verbindungen nach einem der Ansprüche 1 bis 6 zur Verwendung als Arzneimittel.
  8. Verwendung einer Verbindung der Formel (I)
    Figure 00430001
    wobei R1 und R2 jeweils unabhängig voneinander aus Wasserstoff; Hydroxy; Amino; C1-6-Alkyl; C1-6-Alkyloxy; C1-6-Alkylcarbonyl; C1-6-Alkyloxycarbonyl; Ar1; Mono- oder Di(C1-6-alkyl)amino; Mono- oder Di(C1-6-alkyl)aminocarbonyl; Dihydro-2(3H)-furanon; durch einen oder zwei Substituenten unabhängig voneinander ausgewählt aus Amino, Imino, Aminocarbonyl, Aminocarbonylamino, Hydroxy, Hydroxy-C1-6-alkyloxy, Carboxyl, Mono- oder Di(C1-6-alkyl)amino, C1-6-Alkyloxycarbonyl und Thienyl substituiertes C1-6-Alkyl ausgewählt sind; oder
    R1 und R2
    zusammen Pyrrolidinyl, Piperidinyl, Morpholinyl, Azido oder Mono- oder Di(C1-6-alkyl)amino-C1-4-alkyliden bilden können;
    R3
    Wasserstoff, Ar1, C1-6-Alkylcarbonyl, C1-6-Alkyl, C1-6-Alkyloxycarbonyl, durch C1-6-Alkyloxycarbonyl substituiertes C1-6-Alkyl steht; und
    R4, R5, R6, R7 und R8
    jeweils unabhängig voneinander aus Wasserstoff, Hydroxy, Halogen, C1-6-Alkyl, C1-6-Alkyloxy, Cyano, Aminocarbonyl, Nitro, Amino, Trihalogenmethyl oder Trihalogenmethyloxy ausgewählt sind;
    L
    für C1-10- Alkyl; C3-10-Alkenyl; C3-10-Alkinyl; C3-7-Cycloalkyl steht; oder
    L
    für C1-10-Alkyl steht, das durch einen oder zwei Substituenten unabhängig voneinander ausgewählt aus
    • a) C3-7-Cycloalkyl;
    • b) Indolyl oder durch einen, zwei, drei oder vier Substituenten, jeweils unabhängig voneinander ausgewählt aus Halogen, C1-6-Alkyl, C1-6-Alkyloxy, Cyano, Aminocarbonyl, Nitro, Amino, Trihalogenmethyl, Trihalogenmethyloxy, C1-6-Alkylcarbonyl, substituiertes Indolyl;
    • c) Phenyl oder durch einen, zwei, drei, vier oder fünf Substituenten, jeweils unabhängig voneinander ausgewählt aus Halogen, Hydroxy, C1-6-Alkyl, C1-6-Alkyloxy, Cyano, Aminocarbonyl, Nitro, Amino, Trihalogenmethyl, Trihalogenmethyloxy, C1-6-Alkylcarbonyl, substituiertes Phenyl; substituiert ist und
    Ar1
    für Phenyl oder durch einen, zwei oder drei Substituenten, jeweils unabhängig voneinander ausgewählt aus Halogen, C1-6-Alkyl, C1-6-Alkyloxy, Cyano, Nitro oder Trifluormethyl, substituiertes Phenyl steht; zur Herstellung eines Arzneimittels zur Behandlung von Patienten, die an einer HIV-(Human Immunodeficiency Virus-)Infektion leiden.
  9. Verbindungen der Formel
    Figure 00450001
    wobei W5 für Halogen steht und L, R3, R4, R5, R6, R7 und R8 wie in Anspruch 1 definiert sind.
  10. Pharmazeutische Zusammensetzung, enthaltend einen pharmazeutisch unbedenklichen Träger und eine therapeutisch wirksame Menge einer Verbindung nach einem der Ansprüche 1 bis 6.
  11. Verfahren zur Herstellung einer pharmazeutischen Zusammensetzung nach Anspruch 10, dadurch gekennzeichnet, daß man eine therapeutisch wirksame Menge einer Verbindung nach einem der Ansprüche 1 bis 6 innig mit einem pharmazeutisch unbedenklichen Träger mischt.
  12. Verfahren zur Herstellung einer Verbindung nach Anspruch 1, dadurch gekennzeichnet, daß man
    a) ein Zwischenprodukt der Formel (II) in einem reaktionsinerten Lösungsmittel mit einem Zwischenprodukt der Formel (III), wobei R3 bis R8 und L wie in Anspruch 1 definiert sind, unter Bildung einer Verbindung der Formel (I-a) umsetzt;
    Figure 00460001
    b) ein Zwischenprodukt der Formel (IV) in einem reaktionsinerten Lösungsmittel mit einem Zwischenprodukt der Formel (V), wobei R1, R2, R4 bis R8 und L wie in Anspruch 1 definiert sind, unter Bildung einer Verbindung der Formel (I-b) umsetzt;
    Figure 00460002
    c) ein Zwischenprodukt der Formel (VI), wobei n für 1 bis 4 steht und die Reste R' jeweils unabhängig voneinander aus Halogen, C1-6-Alkyl, C1-6-Alkyloxy, Cyano, Aminocarbonyl, Nitro, Amino, Trihalogenmethyl, Trihalogenmethyloxy, C1-6-Alkylcarbonyl ausgewählt sind, nach im Stand der Technik bekannten Entschützungsverfahren unter Bildung einer Verbindung der Formel (I-c) entschützt;
    Figure 00460003
    d) ein Zwischenprodukt der Formel (VII) in einem reaktionsinerten Lösungsmittel und in Gegenwart einer geeigneten Base mit einem Aminoderivat der Formel (VIII), wobei W1 für eine geeignete Abgangsgruppe steht und R2 bis R8 wie in Anspruch 1 definiert sind, umsetzt und, falls R2 eine geschützte Hydroxylgruppe enthält, anschließend die Schutzgruppe nach im Stand der Technik bekannten Verfahren entfernt und so eine Verbindung der Formel (I-d) bildet;
    Figure 00470001
    e) ein Zwischenprodukt der Formel (IX) in einem reaktionsinerten Lösungsmittel unter Bildung einer Verbindung der Formel (I-e) mit einem Zwischenprodukt der Formel (X), wobei W2 für eine geeignete Abgangsgruppe steht und Ar1 und L wie in Anspruch 1 definiert sind, umsetzt;
    Figure 00470002
    f) ein Zwischenprodukt der Formel (XI) in einem reaktionsinerten Lösungsmittel und in Gegenwart einer geeigneten Base unter Bildung einer Verbindung der Formel (I-f-1) mit einem Zwischenprodukt der Formel (XII) umsetzt, wobei W3 für eine geeignete Abgangsgruppe steht, R4 bis R7 wie in Anspruch 1 definiert sind und R1' und R2' die gleichen Werte wie die in Anspruch 1 definierten Reste R1 bzw. R2 haben, jedoch nicht für Wasserstoff stehen;
    Figure 00480001
    g) ein Zwischenprodukt der Formel (XI-b) in einem reaktionsinerten Lösungsmittel und in Gegenwart einer geeigneten Base unter Bildung einer Verbindung der Formel (I-f-2) mit einem Zwischenprodukt der Formel (XII-b) umsetzt, wobei W3 für eine geeignete Abgangsgruppe steht, Ar1 wie in Anspruch 1 definiert ist und R1' und R2' die gleichen Werte wie die in Anspruch 1 definierten Reste R1 und R2 haben, jedoch nicht für Wasserstoff stehen;
    Figure 00480002
    oder, falls gewünscht, Verbindungen der Formel (I') nach im Stand der Technik bekannten Transformationsreaktionen ineinander umwandelt und weiterhin, falls gewünscht, die Verbindungen der Formel (I) durch Behandlung mit einer Säure in ein Säureadditionssalz umwandelt oder umgekehrt die Säureadditionssalzformen durch Behandlung mit Alkali in die freie Base umwandelt und, falls gewünscht, stereochemisch isomere Formen davon herstellt.
  13. Kombination einer wie in Anspruch 8 definierten Verbindung der Formel (I) und einer anderen antiretroviralen Verbindung.
  14. Kombination nach Anspruch 13 zur Verwendung als Medizin.
  15. Produkt, enthaltend (a) eine wie in Anspruch 8 definierte Verbindung der Formel (I)und (b) eine andere antiretrovirale Verbindung, als Kombinationspräparat zur gleichzeitigen, getrennten oder aufeinanderfolgenden Anwendung bei einer Anti-HIV-Behandlung.
  16. Pharmazeutische Zusammensetzung, enthaltend einen pharmazeutisch unbedenklichen Träger und, als Wirkstoffe, (a) eine wie in Anspruch 8 definierte Verbindung der Formel (I) und (b) eine andere antiretrovirale Verbindung.
EP97202917A 1996-10-01 1997-09-24 Substituierte Diamino-1,3,5-Triazinderivate Expired - Lifetime EP0834507B1 (de)

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US7183288B2 (en) 2001-11-01 2007-02-27 Herwig Josephus Margareta Janssen, legal representative Amide derivatives as glycogen synthase kinase 3-β inhibitors
US7449575B2 (en) 1996-10-01 2008-11-11 Janssen Pharmaceutica, Inc. Substituted diamino-1,3,5-triazine derivatives
US7514445B2 (en) 2001-11-01 2009-04-07 Janssen Pharmaceutica N.V. Heteroaryl amines as glycogen synthase kinase 3β inhibitors (GSK3 inhibitors)
US7585861B2 (en) 2003-02-07 2009-09-08 Janssen Pharmaceutica, N.V. HIV inhibiting 1,2,4-triazines
US7763631B2 (en) 2000-05-08 2010-07-27 Janssen Pharmaceutica Nv Prodrugs of HIV replication inhibiting pyrimidines
US7887845B2 (en) 1999-09-24 2011-02-15 Janssen Pharmaceutica Nv Antiviral compositions
US7923554B2 (en) 2004-08-10 2011-04-12 Janssen Pharmaceutica N.V. HIV inhibiting 1,2,4-triazin-6-one derivatives
US8153640B2 (en) 2004-10-29 2012-04-10 Tibotec Pharmaceuticals Ltd. HIV inhibiting bicyclic pyrimdine derivatives
US8318736B2 (en) 2006-12-29 2012-11-27 Janssen R&D Ireland HIV inhibiting 5,6-substituted pyrimidines
US8530655B2 (en) 1998-11-10 2013-09-10 Janssen Pharmaceutica Nv HIV replication inhibiting pyrimidines
US8575342B2 (en) 2004-09-30 2013-11-05 Tibotech Pharmaceuticals Ltd. HIV inhibiting 5-heterocyclyl pyrimidines
US8933089B2 (en) 2006-03-30 2015-01-13 Janssen R & D Ireland HIV inhibiting 5-amido substituted pyrimidines
US8946248B2 (en) 2004-09-30 2015-02-03 Janssen R&D Ireland HIV inhibiting 5-substituted pyrimidines
US9006243B2 (en) 2006-12-29 2015-04-14 Janssen R&D Ireland HIV inhibiting 6-substituted pyrimidines
WO2016059647A3 (en) * 2014-10-13 2016-08-11 SHRI CHHATRAPTI SHIVAJI COLLEGE Maharashtra, India) Triaminotriazine picolinonitrile derivatives as potent reverse transcriptase inhibitor of hiv-1

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DE19945982A1 (de) * 1999-09-24 2001-03-29 Knoll Ag Geschwindigkeitsbestimmte Partikel
JP4794793B2 (ja) * 1999-12-28 2011-10-19 ファーマコペイア， インコーポレイテッド Ｎ−ヘテロ環ＴＮＦ−α発現阻害剤
US6906067B2 (en) 1999-12-28 2005-06-14 Bristol-Myers Squibb Company N-heterocyclic inhibitors of TNF-α expression
CA2406562C (en) * 2000-05-08 2009-09-15 Janssen Pharmaceutica N.V. Hiv replication inhibiting pyrimidines and triazines
EP1409463B1 (de) * 2001-06-26 2010-02-24 Bristol-Myers Squibb Company N-heterocyclische inhibitoren der expression von tnf-alpha
US6958211B2 (en) 2001-08-08 2005-10-25 Tibotech Bvba Methods of assessing HIV integrase inhibitor therapy
EP1513515A2 (de) * 2002-05-16 2005-03-16 Cytovia, Inc. Substitutierte 4h-chromene, 2h-chromene, chromane und analoga als aktivatoren von caspasen und induktoren von apoptose und ihre verwendung
WO2003097806A2 (en) 2002-05-16 2003-11-27 Cytovia, Inc. Substituted 4-aryl-4h-pyrrolo[2,3-h]chromenes and analogs as activators of caspases and inducers of apoptosis and the use thereof
WO2004050068A1 (en) 2002-11-29 2004-06-17 Janssen Pharmaceutica N.V. Pharmaceutical compositions comprising a basic respectively acidic drug compound, a surfactant and a physiologically tolerable water-soluble acid respectively base
CL2004000303A1 (es) * 2003-02-20 2005-04-08 Tibotec Pharm Ltd Compuestos derivados de pirimidinas y triazinas; proceso de preparacion; composicion farmaceutica; y su uso para inhibir la replicacion del vih.
WO2005003103A2 (en) * 2003-06-30 2005-01-13 Astrazeneca Ab 2, 4, 6-tri-substituted 6-membered heterocycles and their use in the treatment of neurodegenerative diseases
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EP1797048B1 (de) 2004-09-30 2011-08-17 Tibotec Pharmaceuticals Hiv-hemmende 5-carbo- oder heterozyklisch substituierte pyrimidine
US8193206B2 (en) 2005-06-14 2012-06-05 Taigen Biotechnology Co., Ltd. Pyrimidine compounds
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CN101679321B (zh) * 2007-04-30 2012-10-03 普罗米蒂克生物科学公司 三嗪衍生物、含所述衍生物的组合物以及所述衍生物在制备用于治疗癌症和自身免疫性疾病药物中的应用
PL2268635T3 (pl) 2008-04-21 2015-11-30 Taigen Biotechnology Co Ltd Związki heterocykliczne
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EP3129359B1 (de) * 2014-04-11 2021-03-03 Basf Se Diaminotriazine-derivate als herbizide
CN105837525B (zh) * 2016-03-25 2019-05-28 浙江工业大学 2,4-二胺-1,3,5-三嗪类化合物及其制备方法与应用

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US7449575B2 (en) 1996-10-01 2008-11-11 Janssen Pharmaceutica, Inc. Substituted diamino-1,3,5-triazine derivatives
US8530655B2 (en) 1998-11-10 2013-09-10 Janssen Pharmaceutica Nv HIV replication inhibiting pyrimidines
US7887845B2 (en) 1999-09-24 2011-02-15 Janssen Pharmaceutica Nv Antiviral compositions
US7763631B2 (en) 2000-05-08 2010-07-27 Janssen Pharmaceutica Nv Prodrugs of HIV replication inhibiting pyrimidines
US7514445B2 (en) 2001-11-01 2009-04-07 Janssen Pharmaceutica N.V. Heteroaryl amines as glycogen synthase kinase 3β inhibitors (GSK3 inhibitors)
US7183288B2 (en) 2001-11-01 2007-02-27 Herwig Josephus Margareta Janssen, legal representative Amide derivatives as glycogen synthase kinase 3-β inhibitors
AU2004213173B2 (en) * 2003-02-07 2010-07-29 Janssen Pharmaceutica N.V. HIV inhibiting 1,2,4-triazines
US7585861B2 (en) 2003-02-07 2009-09-08 Janssen Pharmaceutica, N.V. HIV inhibiting 1,2,4-triazines
US7923554B2 (en) 2004-08-10 2011-04-12 Janssen Pharmaceutica N.V. HIV inhibiting 1,2,4-triazin-6-one derivatives
US8946248B2 (en) 2004-09-30 2015-02-03 Janssen R&D Ireland HIV inhibiting 5-substituted pyrimidines
US8575342B2 (en) 2004-09-30 2013-11-05 Tibotech Pharmaceuticals Ltd. HIV inhibiting 5-heterocyclyl pyrimidines
US8153640B2 (en) 2004-10-29 2012-04-10 Tibotec Pharmaceuticals Ltd. HIV inhibiting bicyclic pyrimdine derivatives
US9487518B2 (en) 2004-10-29 2016-11-08 Janssen Sciences Ireland Uc HIV inhibiting bicyclic pyrimidine derivatives
US9802943B2 (en) 2004-10-29 2017-10-31 Janssen Sciences Ireland Uc HIV inhibiting bicyclic pyrimidine derivatives
US10072015B2 (en) 2004-10-29 2018-09-11 Janssen Sciences Ireland Uc HIV inhibiting bicyclic pyrimidine derivatives
US10077270B2 (en) 2004-10-29 2018-09-18 Janssen Sciences Ireland Uc HIV inhibiting bicyclic pyrimidine derivatives
US8933089B2 (en) 2006-03-30 2015-01-13 Janssen R & D Ireland HIV inhibiting 5-amido substituted pyrimidines
US9573942B2 (en) 2006-03-30 2017-02-21 Janssen Sciences Ireland Uc HIV inhibiting 5-amido substituted pyrimidines
US8318736B2 (en) 2006-12-29 2012-11-27 Janssen R&D Ireland HIV inhibiting 5,6-substituted pyrimidines
US9006243B2 (en) 2006-12-29 2015-04-14 Janssen R&D Ireland HIV inhibiting 6-substituted pyrimidines
WO2016059647A3 (en) * 2014-10-13 2016-08-11 SHRI CHHATRAPTI SHIVAJI COLLEGE Maharashtra, India) Triaminotriazine picolinonitrile derivatives as potent reverse transcriptase inhibitor of hiv-1

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NZ328854A (en) 2000-10-27
IL121849A (en) 2001-08-26
CZ297333B6 (cs) 2006-11-15
AR008864A1 (es) 2000-02-23
HK1009676A1 (en) 1999-06-04
RU2186774C2 (ru) 2002-08-10
CN1083438C (zh) 2002-04-24
IL121849A0 (en) 1998-02-22
US20020147181A1 (en) 2002-10-10
ID19599A (id) 1998-07-23
DE69729153D1 (de) 2004-06-24
US6962916B2 (en) 2005-11-08
HRP970526B1 (en) 2002-10-31
SK285241B6 (sk) 2006-09-07
AU740809B2 (en) 2001-11-15
DE69729153T2 (de) 2005-01-27
US6380194B1 (en) 2002-04-30
SG53075A1 (en) 1998-09-28
NO974368D0 (no) 1997-09-22
NO311614B1 (no) 2001-12-17
PL322369A1 (en) 1998-04-14
OA10620A (en) 2002-09-03
JP4127882B2 (ja) 2008-07-30
CA2216486A1 (en) 1998-04-01
KR19980032428A (ko) 1998-07-25
US6858609B2 (en) 2005-02-22
CZ299397A3 (cs) 1998-11-11
ES2221679T3 (es) 2005-01-01
AP914A (en) 2000-12-18
TR199701070A2 (xx) 1998-04-21
US20030199473A1 (en) 2003-10-23
US7449575B2 (en) 2008-11-11
DK0834507T3 (da) 2004-09-06
US20060189614A1 (en) 2006-08-24
KR100478846B1 (ko) 2006-06-13
PT834507E (pt) 2004-10-29
AU3926697A (en) 1998-04-09
MX9707511A (es) 1998-06-30
EP0834507A1 (de) 1998-04-08
ZA978766B (en) 1999-03-30
EE9700253A (et) 1998-04-15
JPH10114759A (ja) 1998-05-06
TW411335B (en) 2000-11-11
CN1180698A (zh) 1998-05-06
HUP9701596A2 (hu) 1999-06-28
HUP9701596A3 (en) 2000-04-28
HRP970526A2 (en) 1998-10-31
HU9701596D0 (en) 1997-11-28
EE03826B1 (et) 2002-08-15
SI0834507T1 (en) 2004-10-31
HU225270B1 (en) 2006-08-28
PL190155B1 (pl) 2005-11-30
AP9701109A0 (en) 1997-10-31
NO974368L (no) 1998-04-02
ATE267179T1 (de) 2004-06-15
SK131997A3 (en) 1999-06-11
MY123803A (en) 2006-06-30
BR9704937A (pt) 2000-06-06

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